Nonalcoholic steatohepatitis (NASH) characterized by liver steatosis with hepatocellular injury and inflammation is a potentially serious condition with up to 25% of patients progressing to cirrhosis with complications of portal hypertension, liver failure, and hepatocellular carcinoma. NASH is highly prevalent in patients with type 2 diabetes (T2D) and is an escalating health problem due to the global epidemic of T2D. Currently, control of lipids by diet and exercise is the only approved treatment; but long-term effectiveness is questionable because many patients are unable to comply with the required dietary and lifestyle changes, emphasizing the need for an effective pharmacotherapeutic approach. The thiazolidines and vitamin E can improve liver histology in NASH patients; but they are handicapped by formidable adverse effects. The investigational agent, obeticholic acid, has been shown to improve the biochemical and histological features of NASH; but drug safety requires further evaluation in the light of potentially adverse effects on blood lipids. A new compound, ARI-3037MO, can reverse the elevation of the enzyme markers of liver damage in hyperlipidemic hamsters and reduce circulating triglycerides and body weight. ARI-3037MO is a synthetic analog of nicotinic acid (NA), which itself has been reported to reverse hepatic steatosis in a hyperlipidemic model. NA significantly reduced liver lipid in a small clinical trial but clinical acceptance in NAFLD/NASH patients is unlikely given its association with hepatoxicity, impaired insulin sensitivity, and flushing. ARI- 3037MO does not interact with the high affinity receptor for NA, GPR109A, which mediates the latter two adverse effects; but, preclinically and clinically, ARI-3037MO retained beneficial effects on lipid levels and inflammation. ARI-3037MO did not impair glucose control, cause flushing, or show any signs of hepatotoxicity in human phase I trials, suggesting feasibility as a drug candidate in NAFLD/NASH. The next step is to examine efficacy in NAFLD/NASH patients with moderate biopsy-proven steatohepatitis in a 6-month study.
The Specific Aim i s to demonstrate that ARI-3037MO reduces intrahepatic lipid content and improves liver function via beneficial changes in liver function tests. In order to advance into a placebo-controlled, proof-of- concept phase II clinical study in NASH patients (SBIR phase 2), ARI-3037MO must meet specific Benchmarks: 1) at least a 33% reduction in intrahepatic lipid content measured by MRI spectroscopy, and 2) a 25% or greater reduction in the alanine transaminase marker of liver disease. A study director at an advanced clinical site (Beth Israel Deaconess Medical Center), a homogeneous study population selected by liver histology indicative of reversible disease, and the safety profile of ARI-3037MO provide confidence that the study can be successfully executed to yield definitive, measurable outcomes.
Nonalcoholic steatohepatitis (NASH) is an escalating public health problem linked to the global diabetes epidemic and is characterized by liver steatosis accompanied by hepatocellular injury, inflammation and risk of progression to cirrhosis with complications of portal hypertension, liver failure, and hepatocellular carcinoma. Effectiveness of diet and exercise to control NASH is limited by patient compliance; moreover, existing therapeutic agents, such as the thiazolidines and vitamin E, and an otherwise promising investigational agent, obeticholic acid, are handicapped by significant safety concerns. Efficacy of the new investigational agent, ARI-3037MO, will be tested in NAFLD/NASH patients in a trial with intrahepatic lipid, and liver enzyme endpoints.